This invention relates to new 2-oxo-1-azetidine sulfonic acid derivatives which are of value for use in combination with .beta.-lactam antibiotics to increase their effectiveness in infection caused by .beta.-lactamase producing bacteria.
The most important bacterial resistance to .beta.-lactam antibiotics is the degradation of the .beta.-lactam nucleus by production of .beta.-lactamase enzyme. The apparently endless capacity of .beta.-lactamases to develop the ability to degrade the commercially used penicillins and cephalosporins, has led to the alternative strategy of seeking inhibitors to block their action. When a .beta.-lactamase inhibitor is used in combination with a .beta.-lactamase-susceptible .beta.-lactam antibiotic, the effectiveness of the .beta.-lactam antibiotic is increased or enhanced. Such an effect is known as synergy. Synergy is deemed to be exhibited by a combination of .beta.-lactamase inhibitor and a .beta.-lactam antibiotic when the antibacterial activity of the combination is significantly greater than the sum of the antibacterial activities of the individual components.
The present invention provides certain novel 2-oxo-1-azetidine sulfonic acid derivatives which are potent inhibitors of bacterial .beta.-lactamases, particularly against class C .beta.-lactamases (cephalosporinase). U.S. Pat. No. 4,775,670 issued Oct. 4, 1988 to Sykes et al. discloses the discovery of 2-oxo-1-azetidine sulfonic acid salts as antibacterial agents. One member from this series, called aztreonam is a known antibiotic. Several publications [(e.g., Antimicrobial Agents and Chemotherapy, Vol. 22, pp. 414-420, (1982); Chemotherapy, vol. 30, pp. 398-407, (1984); J. Antibiotics, vol. 35, no. 5, pp. 589-593, (1982); J. Antibiotics, vol. 43, no. 4, pp. 403-410, (1990)] suggest that aztreonam possesses .beta.-lactamase inhibitory properties.
Aztreonam is a monocyclic .beta.-lactam having a sulfonic acid substituent in the 1-position and a (substituted oxyimino) acylamino group in the 3-position. The orientation of the "substituted oxyimino" group in aztreonam is in the "Syn" form (Z-isomer).
The present inventors found that by introducing an aminoalkyl substituted "anti" (E-isomer) oxyimino group in the acylamino substituent at 3-position of the monobactam ring, it is possible to obtain a monobactam compound having remarkable .beta.-lactamase inhibitory activity, particularly against class C .beta.-lactamases (cephalosporinase).